Exploring the Impact of Negative Energy Balance in Men with Prostate Cancer Prostate cancer is the leading cancer among US males, and kills more than 33 thousand men annually. Mortality rates are especially high in the southern US, where obesity is pandemic. Obesity and overweight are associated with the risk of aggressive disease, and energy balance may play a major role in prostate cancer progression. Preclinical studies suggest that negative energy balance from both caloric restriction and increased physical activity that results in weight loss may suppress several hormonal and inflammatory factors that drive tumor growth, e.g., leptin, vascular endothelial growth factor (VEGF), phosphatidylinositol 3 kinase (PI3K), and the mammalian target of rapamycin (mTOR), and may ultimately affect tumor proliferation rate and apoptosis. Experiments in humans however have been limited. Our multidisciplinary research team comprised of nutrition, exercise and basic scientists, biostatisticians, and clinicians seeks to conduct a pilot/feasibility study among 40 overweight or obese men newly diagnosed with prostate cancer who are scheduled for prostatectomy. This study will capitalize on our experience of using the presurgical period to explore the potential impact of weight loss via a healthy energy-restricted diet and increased physical activity (PA) on circulating hormones, cytokines, and growth factors, as well as effects on tumor biology and other clinical outcomes. Consenting patients will be block randomized to 1-of-2 study arms: 1) a healthful diet + exercise intervention to promote a weight loss of up to 2 pounds/week; or 2) a wait-list control who will receive the intervention once the study period is complete. This study will explore and contrast changes in body mass index (BMI) observed over the 10-week study period in the intervention vs. wait-list control arms, and also monitor changes in body composition, energy intake and PA; these changes will be studied in relation to the following endpoints: a) changes in select circulating biomarkers and gene expression related to cancer progression, hormonal status, inflammation and other energy-related factors; b) rates of tumor proliferation and apoptosis; c) tumor immunohistochemical markers of insulin receptor, VEGF, AKT, and NFkB; and d) functional and health-related outcomes, i.e., side-effects and medical outcomes , quality of life (QoL), and functional status. Such data are foundational and may ultimately lead to novel complementary therapies in this patient population.